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Aim: The features and outcomes of sepsis-associated acute kidney injury (SA-AKI) may be affected by chronic kidney disease (CKD). Accordingly, we aimed to compare SA-AKI in patients with or without CKD., Methods: Retrospective cohort study in 12 intensive care units (ICU). We studied the prevalence, patient characteristics, timing, trajectory, treatment and outcomes of SA-AKI with and without CKD., Results: Of 84 240 admissions, 7255 (8.6%) involved patients with CKD. SA-AKI was more common in patients with CKD (21% vs 14%; p < .001). CKD patients were older (70 vs. 60 years; p < .001), had a higher median Charlson co-morbidity index (5 vs. 3; p < .001) and acute physiology and chronic health evaluation (APACHE) III score (78 vs. 60; p < .001) and were more likely to receive renal replacement therapy (RRT) (25% vs. 17%; p < .001). They had less complete return to baseline function at ICU discharge (48% vs. 60%; p < .001), higher major adverse kidney events at day 30 (MAKE-30) (38% vs. 27%; p < .001), and higher hospital and 90-day mortality (21% vs. 13%; p < .001, and 27% vs. 16%; p < .001, respectively). After adjustment for patient characteristics and severity of illness, however, CKD was not an independent risk factor for increased 90-day mortality (OR 0.88; 95% CI 0.76-1.02; p = .08) or MAKE-30 (OR 0.98; 95% CI 0.80-1.09; p = .4)., Conclusion: SA-AKI is more common in patients with CKD. Such patients are older, more co-morbid, have higher disease severity, receive different ICU therapies and have different trajectories of renal recovery and greater unadjusted mortality. However, after adjustment day-90 mortality and MAKE-30 risk were not increased by CKD., (© 2024 The Author(s). Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Dysregulation of the renin-angiotensin-aldosterone-system (RAAS) in sepsis is a complex and early phenomenon with a likely significant contribution to organ failure and patient outcomes. A better understanding of the pathophysiology and intricacies of the RAAS in septic shock has led to the use of exogenous angiotensin II as a new therapeutic agent. In this review, we report a multinational and multi-disciplinary expert panel discussion on the role and implications of RAAS modulation in sepsis and the use of exogenous angiotensin II. The panel proposed guidance regarding patient selection and treatment options with exogenous angiotensin II which should trigger further research., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The organization of the consensus meeting was sponsored by Viatris, which commercialized Giapreza. Mathieu Legrand is supported by grant number R01-GM151494-01 from NIGMS/NIH and received consulting fees from Alexion, Radiometer, Viatris and La Jolla. Giovanni Landoni received speaker fees from Medis, Paion and Viatris, and consultancy fees from Paion and Viatris. PMW received consultant fees from Viatris. AKK has previously received consulting fees from La Jolla Pharma, including grant funding for the ATHOS3 trial. He has also previously received consulting fees from Innoviva Therapeutics and Viatris Pharmaceuticals. He is supported by a Wake Forest Cardiovascular Sciences Center Award and a NIH/NCATS Award “Dysfunction Renin in Septic Shock”. He has received consulting fees on advisory boards for Medtronic, Edwards Life Sciences, Philips Research North America, Baxter, GE Healthcare, Potrero Medical, Retia Medical, Pharmazz Inc., Trevena Pharma and Caretaker Medical for activities unrelated to the current manuscript. Katarzyna Kotfis is National Consultant in Anesthesiology and Critical Care in Poland, Associate Editor for Intensive Care Medicine (ISSN 1432-1238), Advisory board member for Critical Care (ISSN: 1364-8535) and Member of the Advisory Board for Viatris. Alexander Zarbock has received consulting fees from Astute-Biomerieux, Baxter, Bayer, Novartis, Guard Therapeutics, AM Pharma, Paion, Viatris, Renibus, Alexion, Fresenius, research funding from Astute-Biomerieux, Fresenius, Baxter, and speakers fees from Astute-Biomerieux, Fresenius, Baxter. Daniel De Backer has received consulting fees from Edwards Lifesciences, Philips, Baxter, Viatris, Pharmazz. Other authors had not disclosures to declare., (© 2024. The Author(s).)

Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre-clinical studies showed benefit with a histone-neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose-adjusted, open-label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady-state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug-related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half-life values ranged from 5 to 7 h. The mean (±SD) terminal half-life for non-RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified., (© 2024 Grand Medical Pty Ltd. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: The mechanisms by which megadose sodium ascorbate improves clinical status in experimental sepsis is unclear. We determined its effects on cerebral perfusion, oxygenation, and temperature, and plasma levels of inflammatory biomarkers, nitrates, nitrites, and ascorbate in ovine Gram-negative sepsis., Methods: Sepsis was induced by i.v. infusion of live Escherichia coli for 31 h in unanaesthetised Merino ewes instrumented with a combination sensor in the frontal cerebral cortex to measure tissue perfusion, oxygenation, and temperature. Fluid resuscitation at 23 h was followed by i.v. megadose sodium ascorbate (0.5 g kg -1 over 30 min+0.5 g kg -1 h -1 for 6.5 h) or vehicle (n=6 per group). Norepinephrine was titrated to restore mean arterial pressure (MAP) to 70-80 mm Hg., Results: At 23 h of sepsis, MAP (mean [sem]: 85 [2] to 64 [2] mm Hg) and plasma ascorbate (27 [2] to 15 [1] μM) decreased (both P<0.001). Cerebral ischaemia (901 [58] to 396 [40] units), hypoxia (34 [1] to 19 [3] mm Hg), and hyperthermia (39.5 [0.1]°C to 40.8 [0.1]°C) (all P<0.001) developed, accompanied by malaise and lethargy. Sodium ascorbate restored cerebral perfusion (703 [121] units], oxygenation (30 [2] mm Hg), temperature (39.2 [0.1]°C) (all P Treatment <0.05), and the behavioural state to normal. Sodium ascorbate slightly reduced the sepsis-induced increase in interleukin-6, returned VEGF-A to normal (both P GroupxTime <0.01), and increased plasma ascorbate (20 000 [300] μM; P Group <0.001). The effects of sodium ascorbate were not reproduced by equimolar sodium bicarbonate., Conclusions: Megadose sodium ascorbate rapidly reversed sepsis-induced cerebral ischaemia, hypoxia, hyperthermia, and sickness behaviour. These effects were not reproduced by an equimolar sodium load., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: To derive a pooled estimate of the incidence and outcomes of sepsis-associated acute kidney injury (SA-AKI) in ICU patients and to explore the impact of differing definitions of SA-AKI on these estimates., Data Sources: Medline, Medline Epub, EMBASE, and Cochrane CENTRAL between 1990 and 2023., Study Selection: Randomized clinical trials and prospective cohort studies of adults admitted to the ICU with either sepsis and/or SA-AKI., Data Extraction: Data were extracted in duplicate. Risk of bias was assessed using adapted standard tools. Data were pooled using a random-effects model. Heterogeneity was assessed by using a single covariate logistic regression model. The primary outcome was the proportion of participants in ICU with sepsis who developed AKI., Data Synthesis: A total of 189 studies met inclusion criteria. One hundred fifty-four reported an incidence of SA-AKI, including 150,978 participants. The pooled proportion of patients who developed SA-AKI across all definitions was 0.40 (95% CI, 0.37-0.42) and 0.52 (95% CI, 0.48-0.56) when only the Risk Injury Failure Loss End-Stage, Acute Kidney Injury Network, and Improving Global Outcomes definitions were used to define SA-AKI. There was significant variation in the incidence of SA-AKI depending on the definition of AKI used and whether AKI defined by urine output criteria was included; the incidence was lowest when receipt of renal replacement therapy was used to define AKI (0.26; 95% CI, 0.24-0.28), and highest when the Acute Kidney Injury Network score was used (0.57; 95% CI, 0.45-0.69; p < 0.01). Sixty-seven studies including 29,455 participants reported at least one SA-AKI outcome. At final follow-up, the proportion of patients with SA-AKI who had died was 0.48 (95% CI, 0.43-0.53), and the proportion of surviving patients who remained on dialysis was 0.10 (95% CI, 0.04-0.17)., Conclusions: SA-AKI is common in ICU patients with sepsis and carries a high risk of death and persisting kidney impairment. The incidence and outcomes of SA-AKI vary significantly depending on the definition of AKI used., Competing Interests: Dr. Bagshaw is supported by a Canada Research Chair in Critical Care Outcomes and Systems Evaluation. Drs. Bagshaw and Hammond received funding from Baxter. Dr. Bagshaw received funding from Novartis, Bioporto, and Sea Star Medical. Dr. Hammond received funding from CSL Behring, Grifols, and Revimmune. Dr. Venkatesh’s institution received funding from Baxter and the National Health and Medical Research Council. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Noradrenaline and metaraminol are commonly used vasopressors in critically ill patients. However, little is known of their dose equivalence., Methods: We conducted a single centre retrospective cohort study of all ICU patients who transitioned from metaraminol to noradrenaline infusions between August 26, 2016 and December 31, 2020. Patients receiving additional vasoactive drug infusion were excluded. Dose equivalence was calculated based on the last hour metaraminol dose (in μg/min) and the first hour noradrenaline dose (in μg/min) with the closest matched mean arterial pressure (MAP). Sensitivity analyses were performed on patients with acute kidney injury (AKI), sepsis and mechanical ventilation., Results: We studied 195 patients. The median conversion ratio of metaraminol to noradrenaline was 12.5:1 (IQR 7.5-20.0) for the overall cohort. However, the coefficient of variation was 77% and standard deviation was 11.8. Conversion ratios were unaffected by sepsis or mechanical ventilation but increased (14:1) with AKI. One in five patients had a MAP decrease of >10 mmHg during the transition period from metaraminol to noradrenaline. Post-transition noradrenaline dose (p < 0.001) and AKI (p = 0.045) were independently associated with metaraminol dose. The proportion of variation in noradrenaline dose predicted from metaraminol dose was low (R 2  = 0.545)., Conclusions: The median dose equivalence for metaraminol and noradrenaline in this study was 12.5:1. However, there was significant variance in dose equivalence, only half the proportion of variation in noradrenaline infusion dose was predicted by metaraminol dose, and conversion-associated hypotension was common., Competing Interests: Declaration of Competing Interest The authors have disclosed that they do not have any conflicts of interest. There are no sources of funding to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: Higher nitric oxide (NO) levels correlate with adverse sepsis outcomes but are challenging to measure. Methemoglobin (MetHb), a measurable product of NO, has not been utilized for risk stratification. Methodology: All patients with sepsis admitted to the intensive care unit (ICU) that had at least one MetHb measurement within 24 h of ICU admission were retrospectively analyzed. We assessed the epidemiology and associations of MetHb with hospital mortality. Results: Among 7724 patients, 1046 qualified. Those with MetHb ≥1.6% showed significantly higher mortality and fewer days alive outside the hospital by day 28. MetHb levels ≥1.6% independently predicted increased 28-day mortality. Conclusion: Our findings suggest MetHb, easily obtainable from arterial blood gases, can significantly enhance sepsis risk stratification.

Purpose: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety., Methods: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition., Results: Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0-24] and 14 [0-24], number of days alive and discharged from the ICU through day 28 were 15 [0-22] and 10 [0-22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group., Conclusion: Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified., (© 2024. The Author(s).)

Purpose of Review: This review aims to explore the relationship between the renin angiotensin system (RAS) and sepsis-associated acute kidney injury (SA-AKI), a common complication in critically ill patients associated with mortality, morbidity, and long-term cardiovascular complications. Additionally, this review aims to identify potential therapeutic approaches to intervene with the RAS and prevent the development of AKI., Recent Findings: Recent studies have provided increasing evidence of RAS alteration during sepsis, with systemic and local RAS disturbance, which can contribute to SA-AKI. Angiotensin II was recently approved for catecholamine resistant vasodilatory shock and has been associated with improved outcomes in selected patients., Summary: SA-AKI is a common condition that can involve disturbances in the RAS, particularly the canonical angiotensin-converting enzyme (ACE) angiotensin-II (Ang II)/angiotensin II receptor 1 (AT-1R) axis. Increased renin levels, a key enzyme in the RAS, have been shown to be associated with AKI and may also guide vasopressor therapy in shock. In patients with high renin levels, angiotensin II administration may reduce renin concentration, improve intra-renal hemodynamics, and enhance signaling through the angiotensin II receptor 1. Further studies are needed to explore the role of the RAS in SA-AKI and the potential for targeted therapies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown., Methods: We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score., Results: We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes., Conclusion: In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Aim: Renal medullary hypoperfusion and hypoxia precede acute kidney injury (AKI) in ovine sepsis. Oxidative/nitrosative stress, inflammation, and impaired nitric oxide generation may contribute to such pathophysiology. We tested whether the antioxidant and anti-inflammatory drug, tempol, may modify these responses., Methods: Following unilateral nephrectomy, we inserted renal arterial catheters and laser-Doppler/oxygen-sensing probes in the renal cortex and medulla. Noanesthetized sheep were administered intravenous (IV) Escherichia coli and, at sepsis onset, IV tempol (IVT; 30 mg kg -1  h -1 ), renal arterial tempol (RAT; 3 mg kg -1  h -1 ), or vehicle., Results: Septic sheep receiving vehicle developed renal medullary hypoperfusion (76 ± 16% decrease in perfusion), hypoxia (70 ± 13% decrease in oxygenation), and AKI (87 ± 8% decrease in creatinine clearance) with similar changes during IVT. However, RAT preserved medullary perfusion (1072 ± 307 to 1005 ± 271 units), oxygenation (46 ± 8 to 43 ± 6 mmHg), and creatinine clearance (61 ± 10 to 66 ± 20 mL min -1 ). Plasma, renal medullary, and cortical tissue malonaldehyde and medullary 3-nitrotyrosine decreased significantly with sepsis but were unaffected by IVT or RAT. Consistent with decreased oxidative/nitrosative stress markers, cortical and medullary nuclear factor-erythroid-related factor-2 increased significantly and were unaffected by IVT or RAT. However, RAT prevented sepsis-induced overexpression of cortical tissue tumor necrosis factor alpha (TNF-α; 51 ± 16% decrease; p = 0.003) and medullary Thr-495 phosphorylation of endothelial nitric oxide synthase (eNOS; 63 ± 18% decrease; p = 0.015)., Conclusions: In ovine Gram-negative sepsis, renal arterial infusion of tempol prevented renal medullary hypoperfusion and hypoxia and AKI and decreased TNF-α expression and uncoupling of eNOS. However, it did not affect markers of oxidative/nitrosative stress, which were significantly decreased by Gram-negative sepsis., (© 2023 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Purpose: The Acute Disease Quality Initiative (ADQI) Workgroup recently released a consensus definition of sepsis-associated acute kidney injury (SA-AKI), combining Sepsis-3 and Kidney Disease Improving Global Outcomes (KDIGO) AKI criteria. This study aims to describe the epidemiology of SA-AKI., Methods: This is a retrospective cohort study carried out in 12 intensive care units (ICUs) from 2015 to 2021. We studied the incidence, patient characteristics, timing, trajectory, treatment, and associated outcomes of SA-AKI based on the ADQI definition., Results: Out of 84,528 admissions, 13,451 met the SA-AKI criteria with its incidence peaking at 18% in 2021. SA-AKI patients were typically admitted from home via the emergency department (ED) with a median time to SA-AKI diagnosis of 1 day (interquartile range (IQR) 1-1) from ICU admission. At diagnosis, most SA-AKI patients (54%) had a stage 1 AKI, mostly due to the low urinary output (UO) criterion only (65%). Compared to diagnosis by creatinine alone, or by both UO and creatinine criteria, patients diagnosed by UO alone had lower renal replacement therapy (RRT) requirements (2.8% vs 18% vs 50%; p < 0.001), which was consistent across all stages of AKI. SA-AKI hospital mortality was 18% and SA-AKI was independently associated with increased mortality. In SA-AKI, diagnosis by low UO only, compared to creatinine alone or to both UO and creatinine criteria, carried an odds ratio of 0.34 (95% confidence interval (CI) 0.32-0.36) for mortality., Conclusion: SA-AKI occurs in 1 in 6 ICU patients, is diagnosed on day 1 and carries significant morbidity and mortality risk with patients mostly admitted from home via the ED. However, most SA-AKI is stage 1 and mostly due to low UO, which carries much lower risk than diagnosis by other criteria., (© 2023. The Author(s).)

Importance: Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes., Objective: To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis., Design, Setting, and Participants: A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022., Interventions: Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304)., Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events., Results: All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients)., Conclusions and Relevance: In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28., Trial Registration: ClinicalTrials.gov Identifier: NCT03452839.

Sepsis-associated acute kidney injury (SA-AKI) is common in critically ill patients and is strongly associated with adverse outcomes, including an increased risk of chronic kidney disease, cardiovascular events and death. The pathophysiology of SA-AKI remains elusive, although microcirculatory dysfunction, cellular metabolic reprogramming and dysregulated inflammatory responses have been implicated in preclinical studies. SA-AKI is best defined as the occurrence of AKI within 7 days of sepsis onset (diagnosed according to Kidney Disease Improving Global Outcome criteria and Sepsis 3 criteria, respectively). Improving outcomes in SA-AKI is challenging, as patients can present with either clinical or subclinical AKI. Early identification of patients at risk of AKI, or at risk of progressing to severe and/or persistent AKI, is crucial to the timely initiation of adequate supportive measures, including limiting further insults to the kidney. Accordingly, the discovery of biomarkers associated with AKI that can aid in early diagnosis is an area of intensive investigation. Additionally, high-quality evidence on best-practice care of patients with AKI, sepsis and SA-AKI has continued to accrue. Although specific therapeutic options are limited, several clinical trials have evaluated the use of care bundles and extracorporeal techniques as potential therapeutic approaches. Here we provide graded recommendations for managing SA-AKI and highlight priorities for future research., (© 2023. Springer Nature Limited.)

Introduction: Sepsis, the leading cause of acute kidney injury (AKI), is associated with a high morbidity and mortality. Alkaline phosphatase (ALP) is an endogenous detoxifying enzyme. A recombinant human ALP compound, ilofotase alfa, showed no safety or tolerability concerns in a phase 2 trial. Renal function improvement over 28 days was significantly greater in the ilofotase alfa group. Moreover, a significant relative reduction in 28-day all-cause mortality of >40% was observed. A follow-up trial has been designed to confirm these findings., Methods and Analysis: This is a phase 3, global, multi-centre, randomised, double-blind, placebo-controlled, sequential design trial in which patients are randomly assigned to either placebo or 1.6 mg/kg ilofotase alfa. Randomisation is stratified by baseline modified Sequential Organ Failure Assessment (mSOFA) score and trial site. The primary objective is to confirm the survival benefit with ilofotase alfa by demonstrating a reduction in 28-day all-cause mortality in patients with sepsis-associated AKI requiring vasopressors. A maximum of 1400 patients will be enrolled at ∼120 sites in Europe, North America, Japan, Australia and New Zealand. Up to four interim analyses will take place. Based on predefined decision rules, the trial may be stopped early for futility or for effectiveness. In addition, patients with COVID-19 disease and patients with 'moderate to severe' chronic kidney disease are analysed as 2 separate cohorts of 100 patients each. An independent Data Monitoring Committee evaluates safety data at prespecified intervals throughout the trial., Ethics and Dissemination: The trial is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will determine the potential of ilofotase alfa to reduce mortality in critically ill patients with sepsis-associated AKI and will be published in a peer-reviewed scientific journal., Trial Registration Number: EudraCT CT Number 2019-0046265-24. US IND Number 117 605 Pre-results., Clinicaltrials: gov number: NCT04411472., Competing Interests: Competing interests: PP received advisory board consultancy and travel reimbursements from AM-Pharma. DCA and CJD serve as advisory board consultants for AM-Pharma. JA, EvdB and JB are employees of AM-Pharma. RB, MB, KD, BF, JAK, P-FL, VP and PY received advisory board consultancy reimbursements from AM Pharma. KB worked as an employee of Berry Consultants KB and acted as a consultant to numerous pharmaceutical and device companies. KB is currently an employee of and holds stock in AstraZeneca. JC, ALK and SR are consultants to AM-Pharma. RF received advisory board consultancy reimbursements from AM Pharma and additional consulting reimbursements from BioMerieux, Baxter, Pfizer, MSD, Gilead, Shionogi, Grifols and Beckton Dickinson unrelated to the current study. MJ received advisory board consultancy reimbursements from AM Pharma, additional consulting reimbursement from Baxter and Gilead and grant support from Fresenius and Baxter, unrelated to the current study. KL received advisory board consultancy reimbursements from AM-Pharma, owns stock in Amgen and consultant for Biomerieux, Neumora, Seastar and BOA Medical. RLM received advisory board consultancy reimbursements from AM Pharma and additional consulting reimbursement from BioMerieux, Baxter, Nova Biomed, Abiomed, GE Healthcare, Medtronic, Sanofi and Mallinckrodt, unrelated to the current study. PTM received Trial Steering Committee consultancy payments from AM-Pharma. Other consultancy payments: FAST Biomedical, Novartis, Renibus Therapeutics. MO received speaker honoraria from Fresenius Medical Care, Biomerieux, Baxter and Gilead, and research funding from Fresenius Medical Care, Biomerieux, Baxter and LaJolla Pharma and advisory board consultancy reimbursements from AM-Pharma. AZ received advisory board consultancy reimbursements from AM-Pharma. AZ has received consulting and/or lecture fees from Astute Medical/BioMerieux, Fresenius, Paion, Guard Therapeutics, and Baxter, unrelated to the current study. AZ has received grant support from Astute Medical/BioMerieux, Fresenius and Baxter, unrelated to the current study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Hemoadsorption has emerged as an adjunctive therapy for sepsis, but its impact on antibiotic levels remains poorly defined. We conducted an in vivo experimental study to investigate the removal of vancomycin and gentamicin during hemoadsorption using the HA380 cartridge, a novel styrene-divinylbenzene copolymer cartridge., Methods: Six surgically prepared sheep were administered 2 g of vancomycin and 400 mg of gentamicin over 30 min, followed by a continuous infusion of vancomycin (20 mg/h). Hemoadsorption was implemented with a styrene-divinylbenzene copolymer HA380 cartridge at a blood flow of 120 mL/min. The removal ratio, sorbent-based clearance, and the mass removal rate were calculated for each time point., Results: The mean 10-min vancomycin removal ratio exceeded 90% and declined to 68.0% at 30 min; 52.8% at 60 min, and 28.0% by 4 h. Due to constant plasma flow, clearance varied proportionally with the removal ratio. Over 4 hours, the total mass removal was 556 mg (SD 106.3). For gentamicin, the mean 10-min removal ratio was 96.9% and the final ratio at 4 h remained 53.0%, with clearances changing proportionately. The total mass removal of gentamicin was 138 mg (SD 26.6) over 4 h. The sorbent-based clearance of vancomycin was significantly lower than that of gentamicin (Pgroup &lt; 0.0001)., Conclusion: The novel HA380 sorbent cartridge appears safe and achieves significant vancomycin and gentamicin removal over a four-hour period. This information can be used by clinicians to guide their prescription and consider the additional dosing of at least an extra 25-35% amount in patients receiving HA380 hemoadsorption therapy during sepsis., (© 2023 S. Karger AG, Basel.)

Recent development in sorbent technology has spurred new interest in the potential of hemoperfusion (HP) in clinical conditions such as cytokine release syndromes and sepsis. Although the role of nonselective HP in such conditions requires solid evidence and more studies, the rationale for clinical application is clearly emerging. Greater biocompatibility and safety of the new sorbents may allow easy and safe application of HP in those conditions where the innate and the adaptive immune response of the individual appears to be dysregulated. Recent results in small studies seem to confirm the plausibility for this therapeutic approach. The concept suggested by the peak concentration hypothesis justifies new studies and the application of HP in selected patients to remove the peaks of circulating mediators responsible for conditions of hyperinflammation or immunodepression., (© 2023 S. Karger AG, Basel.)

After initial tentative steps with bioincompatible sorbents, hemoadsorption is making a comeback. This has been fueled by improved coating technology and improved sorbent technology. Both have markedly increased the safety, biocompatibility, and efficiency of hemoadsorption. Despite such development and an emerging body of evidence, the research agenda for hemoadsorption is substantial and, in most ways, unfulfilled. In this chapter, we highlight the need for more extensive and sophisticated work to understand the biological effect of hemoadsorption in key areas (especially sepsis). We also explain why more technical research needs to be conducted ex vivo and in large animals to understand the performance characteristics of hemoadsorption sorbent cartridge, including optimal blood flow, optimal anticoagulation, and optimal duration of application. Finally, we focus on the need to develop registries of the use of this technique so that more extensive information can be obtained about current use and real-world performance., (© 2023 S. Karger AG, Basel.)

The Jafron series of sorbent cartridges provides a comprehensive array of coated, highly biocompatible sorbent beads made of styrene-divinylbenzene copolymers. Such beads carry a mean diameter of 0.8 mm with a range from 0.60 to 1.18 mm. The maximal pore size of these coated beads and the volume of the cartridge vary according to the type of cartridge ranging between 50 Da and 60 kDa. The sorbents, the size of the cartridge, the volume of sorbent, and the pore size (which reaches 60 kDa with the HA330 cartridge) aim to take advantage of the principles of molecular adsorption in a variety of diseases from uremic toxin retention to poisoning and drug overdose, from kidney disease to liver failure, from acute respiratory distress syndrome to sepsis, from toxic skin injury to COVID-19. The preliminary data from ex vivo studies, animal investigations, and human pilot work look promising and justify a program of systematic investigation of these products to advance our understanding of how they may be incorporated into our therapeutic arsenal., (© 2023 S. Karger AG, Basel.)

Sorbents have been utilized in the past for intoxication and poisoning, but their spectrum of clinical application is now expanding. Hemoadsorption (HA) is still indicated for toxin and poison removal, but other molecules are considered appropriate targets for this blood purification modality. HA combined with hemodialysis (HA + HD) has been proposed for end-stage kidney disease patients to remove molecules that are not easily removed by classic HD or hemodiafiltration. More recently, a rationale for the use of sorbents in critical illness, sepsis, and acute kidney injury has emerged due to the proposed humoral theory behind these disorders. Pathogenetic circulating molecules in critical illness (damage- and pathogen-associated molecular patterns) cannot be sufficiently removed by classic continuous renal replacement therapies. New sorbent-based extracorporeal therapies have therefore been designed to remove these molecules, offering potential biological and clinical benefits. There is also the possibility of employing selective sorbents to target specific molecules or to perform nonspecific HA for a wide spectrum of molecules. Moreover, there is the possibility of separating plasma from blood and then applying adsorption to plasma or of combining HA with other extracorporeal therapies. Here, we describe a complete appraisal of current available techniques utilizing adsorption., (© 2023 S. Karger AG, Basel.)

The renin-angiotensin-aldosterone system (RAAS), whose major vasopressor effector is angiotensin II (ATII), has multiple activities and regulates sodium-water homeostasis and fluid and blood pressure homeostasis. RAAS plays a crucial role in cardiocirculatory shock because it counteracts hypotension and hypovolemia by activating different physiologic responses. Based on the encouraging results of the ATHOS-3 trial, the US Food and Drug Administration and the European Medicines Agency approved the use of ATII for catecholamine-resistant vasodilatory shock. More recently, ATII was used for the compassionate treatment of critically ill patients with COVID-19. Beyond its vasopressor properties, ATII was hypothesized to have antiviral activity because it induces internalization and degradation of angiotensin-converting enzyme 2 receptors used by SARS-Cov-2 to infect cells. Overall, the use of ATII in patients with COVID-19 showed promising results because its administration was associated with the achievement and maintenance of target mean arterial pressure, increased P a O 2 /F I O 2 ratio, and decreased F I O 2 . The aim of this narrative review is to summarize the available knowledge on the use of ATII in patients with COVID-19., Competing Interests: Conflict of Interest Alexander Zarbock received honorariums and research grants from Fresenius, Baxter, Astellas, AM Pharma, Paion, Guard Therapeutics, Novartis, Bayer, BioMerieux, GIF, BMBF, and DFG. Giovanni Landoni received speaker fees from Paion., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sepsis, defined as organ dysfunction caused by a dysregulated host-response to infection, is characterized by immunosuppression. The vasopressor norepinephrine is widely used to treat low blood pressure in sepsis but exacerbates immunosuppression. An alternative vasopressor is angiotensin-II, a peptide hormone of the renin-angiotensin system (RAS), which displays complex immunomodulatory properties that remain unexplored in severe infection. In a murine cecal ligation and puncture (CLP) model of sepsis, we found alterations in the surface levels of RAS proteins on innate leukocytes in peritoneum and spleen. Angiotensin-II treatment induced biphasic, angiotensin-II type 1 receptor (AT1R)-dependent modulation of the systemic inflammatory response and decreased bacterial counts in both the blood and peritoneal compartments, which did not occur with norepinephrine treatment. The effect of angiotensin-II was preserved when treatment was delivered remote from the primary site of infection. At an independent laboratory, angiotensin-II treatment was compared in LysM-Cre AT1aR -/- (Myeloid-AT1a - ) mice, which selectively do not express AT1R on myeloid-derived leukocytes, and littermate controls (Myeloid-AT1a + ). Angiotensin-II treatment significantly reduced post-CLP bacteremia in Myeloid-AT1a + mice but not in Myeloid-AT1a - mice, indicating that the AT1R-dependent effect of angiotensin-II on bacterial clearance was mediated through myeloid-lineage cells. Ex vivo, angiotensin-II increased post-CLP monocyte phagocytosis and ROS production after lipopolysaccharide stimulation. These data identify a mechanism by which angiotensin-II enhances the myeloid innate immune response during severe systemic infection and highlight a potential role for angiotensin-II to augment immune responses in sepsis.

Purpose of Review: Several studies have recently explored the effects of intravenous vitamin C in sepsis. We aimed to summarize their findings to provide perspectives for future research., Recent Findings: Sepsis trials examined 6 g/day of intravenous vitamin C with or without the thiamine and/or hydrocortisone compared with placebo or hydrocortisone. Network meta-analysis reported that intravenous vitamin C, thiamine, hydrocortisone, or combinations of these drugs was not proven to reduce long-term mortality. However, the component network meta-analysis suggested an association of high-dose (>6 g/day) and very-high dose vitamin C (>12 g/day) and decreased mortality but with low certainty. The preclinical investigations have, however, advanced to much higher doses of intravenous vitamin C therapy since a scoping review on harm reported that mega-doses of intravenous vitamin C (50-100 g/day) had been administered without any conclusive adverse effects. In a Gram-negative sheep model, renal tissue hypoperfusion was reversed, followed by improvements in kidney function when a mega-dose of vitamin C (150 g/day equivalent) was administered., Summary: The effect of intravenous vitamin C in critically ill patients has yet to be determined and might be dose-dependent. Clinical studies of very high or mega doses of vitamin C are justified by preclinical data., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Data on long-term outcomes after sepsis-associated critical illness have mostly come from small cohort studies, with no information about the incidence of new disability. We investigated whether sepsis-associated critical illness was independently associated with new disability at 6 months after ICU admission compared with other types of critical illness., Methods: We conducted a secondary analysis of a multicenter, prospective cohort study in six metropolitan intensive care units in Australia. Adult patients were eligible if they had been admitted to the ICU and received more than 24 h of mechanical ventilation. There was no intervention., Results: The primary outcome was new disability measured with the WHO Disability Assessment Schedule 2.0 (WHODAS) 12 level score compared between baseline and 6 months. Between enrollment and follow-up at 6 months, 222/888 (25%) patients died, 100 (35.5%) with sepsis and 122 (20.1%) without sepsis (P < 0.001). Among survivors, there was no difference for the incidence of new disability at 6 months with or without sepsis, 42/106 (39.6%) and 106/300 (35.3%) (RD, 0.00 (- 10.29 to 10.40), P = 0.995), respectively. In addition, there was no difference in the severity of disability, health-related quality of life, anxiety and depression, post-traumatic stress, return to work, financial distress or cognitive function., Conclusions: Compared to mechanically ventilated patients of similar acuity and length of stay without sepsis, patients with sepsis admitted to ICU have an increased risk of death, but survivors have a similar risk of new disability at 6 months. Trial registration NCT03226912, registered July 24, 2017., (© 2022. The Author(s).)

Background: Blood purification through the removal of plasma solutes by adsorption to beads of charcoal or resins contained in a cartridge (hemoperfusion) has a long and imperfect history. Developments in production and coating technology, however, have recently increased the biocompatibility of sorbents and have spurred renewed interest in hemoperfusion., Methods: We performed a narrative assessment of the literature with focus on the technology, characteristics, and principles of hemoperfusion. We assessed publications in ex vivo, animal, and human studies. We synthesized such literature in a technical and state-of-the-art summary., Results: Early hemoperfusion studies were hampered by bioincompatibility. Recent technology, however, has improved its safety. Hemoperfusion has been used with positive effects in chronic dialysis and chronic liver disease. It has also demonstrated extraction of a variety of toxins and drugs during episodes of overdose. Trials with endotoxin binding polymyxin B have shown mixed results in septic shock and are under active investigation. The role of non-selective hemoperfusion in sepsis or inflammation remains. Although new technologies have made sorbents more biocompatible, the research agenda in the field remains vast., Conclusion: New sorbents markedly differ from those used in the past because of greater biocompatibility and safety. Initial studies of novel sorbent-based hemoperfusion show some promise in specific chronic conditions and some acute states. Systematic studies of novel sorbent-based hemoperfusion are now both necessary and justified., (© 2022. The Author(s).)

Rationale: Hypercapnia may affect the outcome of sepsis. Very few clinical studies conducted in noncritically ill patients have investigated the effects of hypercapnia and hypercapnic acidemia in the context of sepsis. The effect of hypercapnia in critically ill patients with sepsis remains inadequately studied. Objectives: To investigate the association of hypercapnia with hospital mortality in critically ill patients with sepsis. Methods: This is a retrospective study conducted in three tertiary public hospitals. Critically ill patients with sepsis from three intensive care units between January 2011 and May 2019 were included. Five cohorts (exposure of at least 24, 48, 72, 120, and 168 hours) were created to account for immortal time bias and informative censoring. The association between hypercapnia exposure and hospital mortality was assessed with multivariable models. Subgroup analyses compared ventilated versus nonventilated and pulmonary versus nonpulmonary sepsis patients. Results: We analyzed 84,819 arterial carbon dioxide pressure measurements in 3,153 patients (57.6% male; median age was 62.5 years). After adjustment for key confounders, both in mechanically ventilated and nonventilated patients and in patients with pulmonary or nonpulmonary sepsis, there was no independent association of hypercapnia with hospital mortality. In contrast, in ventilated patients, the presence of prolonged exposure to both hypercapnia and acidemia was associated with increased mortality (highest odds ratio of 16.5 for ⩾120 hours of potential exposure; P  = 0.007). Conclusions: After adjustment, isolated hypercapnia was not associated with increased mortality in patients with sepsis, whereas prolonged hypercapnic acidemia was associated with increased risk of mortality. These hypothesis-generating observations suggest that as hypercapnia is not an independent risk factor for mortality, trials of permissive hypercapnia avoiding or minimizing acidemia in sepsis may be safe.

We aimed to compare the effects of vitamin C, glucocorticoids, vitamin B1, combinations of these drugs, and placebo or usual care on longer-term mortality in adults with sepsis or septic shock. MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and WHO-ICTRP were searched. The final search was carried out on September 3rd, 2021. Multiple reviewers independently selected randomized controlled trials (RCTs) comparing very-high-dose vitamin C (≥ 12 g/day), high-dose vitamin C (< 12, ≥ 6 g/day), vitamin C (< 6 g/day), glucocorticoid (< 400 mg/day of hydrocortisone), vitamin B1, combinations of these drugs, and placebo/usual care. We performed random-effects network meta-analysis and, where applicable, a random-effects component network meta-analysis. We used the Confidence in Network Meta-Analysis framework to assess the degree of treatment effect certainty. The primary outcome was longer-term mortality (90-days to 1-year). Secondary outcomes were severity of organ dysfunction over 72 h, time to cessation of vasopressor therapy, and length of stay in intensive care unit (ICU). Forty-three RCTs (10,257 patients) were eligible. There were no significant differences in longer-term mortality between treatments and placebo/usual care or between treatments (10 RCTs, 7,096 patients, moderate to very-low-certainty). We did not find any evidence that vitamin C or B1 affect organ dysfunction or ICU length of stay. Adding glucocorticoid to other treatments shortened duration of vasopressor therapy (incremental mean difference, - 29.8 h [95% CI - 44.1 to - 15.5]) and ICU stay (incremental mean difference, - 1.3 days [95% CI - 2.2 to - 0.3]). Metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs was not significantly associated with a decrease in longer-term mortality., (© 2021. The Author(s).)

Sepsis induced by bacteria or viruses can result in multiorgan dysfunction, which is a major cause of death in intensive care units. Current treatments are only supportive, and there are no treatments that reverse the pathophysiological effects of sepsis. Vitamin C has antioxidant, anti-inflammatory, anticoagulant and immune modulatory actions, so it is a rational treatment for sepsis. Here, we summarise data that support the use of megadose vitamin C as a treatment for sepsis and COVID-19. Megadose intravenous sodium ascorbate (150 g per 40 kg over 7 h) dramatically improved the clinical state and cardiovascular, pulmonary, hepatic and renal function and decreased body temperature, in a clinically relevant ovine model of Gram-negative bacteria-induced sepsis. In a critically ill COVID-19 patient, intravenous sodium ascorbate (60 g) restored arterial pressure, improved renal function and increased arterial blood oxygen levels. These findings suggest that megadose vitamin C should be trialled as a treatment for sepsis and COVID-19., (© 2021 The British Pharmacological Society.)

Agonists of α 2 -adrenoceptors are increasingly being used for the provision of comfort, sedation and the management of delirium in critically ill patients, with and without sepsis. In this context, increased sympathetic and inflammatory activity are common pathophysiological features linked to multi-organ dysfunction, particularly in patients with sepsis or those undergoing cardiac surgery requiring cardiopulmonary bypass. Experimental and clinical studies support the notion that the α 2 -adrenoceptor agonists, dexmedetomidine and clonidine, mitigate sympathetic and inflammatory overactivity in sepsis and cardiac surgery requiring cardiopulmonary bypass. These effects can protect vital organs, including the cardiovascular system, kidneys, heart and brain. We review the pharmacodynamic mechanisms by which α 2 -adrenoceptor agonists might mitigate multi-organ dysfunction arising from pathophysiological conditions associated with excessive inflammatory and adrenergic stress in experimental studies. We also outline recent clinical trials that have examined the use of dexmedetomidine in critically ill patients with and without sepsis and in patients undergoing cardiac surgery., (© 2021 The British Pharmacological Society.)

Objectives: Oxidative stress appears to initiate organ failure in sepsis, justifying treatment with antioxidants such as vitamin C at megadoses. We have therefore investigated the safety and efficacy of megadose sodium ascorbate in sepsis., Design: Interventional study., Setting: Research Institute., Subjects: Adult Merino ewes., Interventions: Sheep were instrumented with pulmonary and renal artery flow-probes, and laser-Doppler and oxygen-sensing probes in the kidney. Conscious sheep received an infusion of live Escherichia coli for 31 hours. At 23.5 hours of sepsis, sheep received fluid resuscitation (30 mL/kg, Hartmann solution) and were randomized to IV sodium ascorbate (0.5 g/kg over 0.5 hr + 0.5 g/kg/hr for 6.5 hr; n = 5) or vehicle (n = 5). Norepinephrine was titrated to restore mean arterial pressure to baseline values (~80 mm Hg)., Measurements and Main Results: Sepsis-induced fever (41.4 ± 0.2°C; mean ± se), tachycardia (141 ± 2 beats/min), and a marked deterioration in clinical condition in all cases. Mean arterial pressure (86 ± 1 to 67 ± 2 mm Hg), arterial Po2 (102.1 ± 3.3 to 80.5 ± 3.4 mm Hg), and renal medullary tissue Po2 (41 ± 5 to 24 ± 2 mm Hg) decreased, and plasma creatinine doubled (71 ± 2 to 144 ± 15 µmol/L) (all p < 0.01). Direct observation indicated that in all animals, sodium ascorbate dramatically improved the clinical state, from malaise and lethargy to a responsive, alert state within 3 hours. Body temperature (39.3 ± 0.3°C), heart rate (99.7 ± 3 beats/min), and plasma creatinine (32.6 ± 5.8 µmol/L) all decreased. Arterial (96.5 ± 2.5 mm Hg) and renal medullary Po2 (48 ± 5 mm Hg) increased. The norepinephrine dose was decreased, to zero in four of five sheep, whereas mean arterial pressure increased (to 83 ± 2 mm Hg). We confirmed these physiologic findings in a coronavirus disease 2019 patient with shock by compassionate use of 60 g of sodium ascorbate over 7 hours., Conclusions: IV megadose sodium ascorbate reversed the pathophysiological and behavioral responses to Gram-negative sepsis without adverse side effects. Clinical studies are required to determine if such a dose has similar benefits in septic patients., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

In sepsis-induced acute kidney injury, kidney blood flow may increase despite decreased glomerular filtration. Normally, angiotensin-II reduces kidney blood flow to maintain filtration. We hypothesized that sepsis reduces angiotensin type-1 receptor (AT1R) expression to account for this observation and tested this hypothesis in a patient case-control study and studies in mice. Seventy-three mice underwent cecal ligation and puncture (a sepsis model) or sham operation. Additionally, 94 septic mice received losartan (selective AT1R antagonist), angiotensin II without or with losartan, or vehicle. Cumulative urine output, kidney blood flow, blood urea nitrogen, and creatinine were measured. AT1R expression was assessed using ELISA, qPCR, and immunofluorescence. A blinded pathologist evaluated tissue for ischemic injury. AT1R expression was compared in autopsy tissue from seven patients with sepsis to that of the non-involved portion of kidney from ten individuals with kidney cancer and three non-infected but critically ill patients. By six hours post ligation/puncture, kidney blood flow doubled, blood urea nitrogen rose, and urine output fell. Concurrently, AT1R expression significantly fell 2-fold in arterioles and the macula densa. Creatinine significantly rose by 24 hours and sham operation did not alter measurements. Losartan significantly exacerbated ligation/puncture-induced changes in kidney blood flow, blood urea nitrogen, creatinine, and urine output. There was no histologic evidence of cortical ischemia. Significantly, angiotensin II prevented changes in kidney blood flow, creatinine, and urine output compared to vehicle. Co-administering losartan with angiotensin-II reversed this protection. Relative to both controls, patients with sepsis had low AT1R expression in arterioles and macula densa. Thus, murine cecal ligation/puncture and clinical sepsis decrease renal AT1R expression. Angiotensin II prevents functional changes while AT1R-blockade exacerbates them independent of ischemia in mice., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objectives: To compare the effects of restoring mean arterial pressure with vasopressin or norepinephrine on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, and renal function in ovine septic acute kidney injury., Design: Interventional Study., Setting: Research Institute., Subjects: Adult Merino ewes., Interventions: Flow probes were implanted on the pulmonary and renal arteries (and the mesenteric artery in sheep that received vasopressin). Fiber-optic probes were implanted in the renal cortex and medulla to measure tissue perfusion and oxygen tension (PO2). Conscious sheep were administered Escherichia coli to induce septic acute kidney injury. Vasopressin (0.03 IU/min [0.03-0.05 IU/min]; n = 7) or norepinephrine (0.60 μg/kg/min [0.30-0.70 μg/kg/min]; n = 7) was infused IV and titrated to restore baseline mean arterial pressure during 24-30 hours of sepsis., Measurements and Main Results: Ovine septic acute kidney injury was characterized by reduced mean arterial pressure (-16% ± 2%) and creatinine clearance (-65% ± 9%) and increased renal blood flow (+34% ± 7%) but reduced renal medullary perfusion (-44% ± 7%) and PO2 (-47% ± 10%). Vasopressin infusion did not significantly affect renal medullary perfusion or PO2 and induced a sustained (6 hr) ~2.5-fold increase in creatinine clearance. Vasopressin reduced sepsis-induced mesenteric hyperemia (+61 ± 13 to +9% ± 6%). Norepinephrine transiently (2 hr) improved creatinine clearance (by ~3.5-fold) but worsened renal medullary ischemia (to -64% ± 7%) and hypoxia (to -71% ± 6%)., Conclusions: In ovine septic acute kidney injury, restoration of mean arterial pressure with vasopressin induced a more sustained improvement in renal function than norepinephrine, without exacerbating renal medullary ischemia and hypoxia or reducing mesenteric blood flow below baseline values.

Objective: Despite wide interest in glycocalyx biomarkers, their values in healthy individuals, patients after abdominal surgery, and septic patients have been poorly understood., Methods: We searched MEDLINE, CENTRAL and EMBASE for papers measured glycocalyx biomarkers in healthy individuals, patients after abdominal surgery and septic patients., Results: We extracted 3948 titles and identified 58 eligible papers. Syndecan 1 was the most frequently measured biomarker (48 studies). Its mean or median value in healthy individuals varied to a biologically implausible degree, from 0.3 to 58.5 ng/ml, according to assay manufacturer. In post-operative patients, syndecan 1 levels increased after pancreatic surgery or liver surgery, however, they showed minor changes after hysterectomy or laparoscopic surgery. In septic patients, biomarker levels were higher than in healthy volunteers when using the same assay. However, six healthy volunteer studies reported higher syndecan 1 values than after pancreatic surgery and 24 healthy volunteer studies reported higher syndecan 1 values than the lowest syndecan 1 value in sepsis. Similar findings applied to other glycocalyx biomarkers., Conclusion: Glycocalyx damage biomarkers values are essentially defined by syndecan 1. Syndecan 1 levels, however, are markedly affected by assay type and show biologically implausible values in normal, post-operative, or septic subjects.

Objectives: To describe haemodynamic resuscitation practices in ED patients with suspected sepsis and hypotension., Methods: This was a prospective, multicentre, observational study conducted in 70 hospitals in Australia and New Zealand between September 2018 and January 2019. Consecutive adults presenting to the ED during a 30-day period at each site, with suspected sepsis and hypotension (systolic blood pressure <100 mmHg) despite at least 1000 mL fluid resuscitation, were eligible. Data included baseline demographics, clinical and laboratory variables and intravenous fluid volume administered, vasopressor administration at baseline and 6- and 24-h post-enrolment, time to antimicrobial administration, intensive care admission, organ support and in-hospital mortality., Results: A total of 4477 patients were screened and 591 were included with a mean (standard deviation) age of 62 (19) years, Acute Physiology and Chronic Health Evaluation II score 15.2 (6.6) and a median (interquartile range) systolic blood pressure of 94 mmHg (87-100). Median time to first intravenous antimicrobials was 77 min (42-148). A vasopressor infusion was commenced within 24 h in 177 (30.2%) patients, with noradrenaline the most frequently used (n = 138, 78%). A median of 2000 mL (1500-3000) of intravenous fluids was administered prior to commencing vasopressors. The total volume of fluid administered from pre-enrolment to 24 h was 4200 mL (3000-5661), with a range from 1000 to 12 200 mL. Two hundred and eighteen patients (37.1%) were admitted to an intensive care unit. Overall in-hospital mortality was 6.2% (95% confidence interval 4.4-8.5%)., Conclusion: Current resuscitation practice in patients with sepsis and hypotension varies widely and occupies the spectrum between a restricted volume/earlier vasopressor and liberal fluid/later vasopressor strategy., (© 2020 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Purpose: Sepsis is a common reason for intensive care unit (ICU) admission and mortality in ICU patients. Despite increasing interest in treatment strategies limiting oxygen exposure in ICU patients, no trials have compared conservative vs. usual oxygen in patients with sepsis., Methods: We undertook a post hoc analysis of the 251 patients with sepsis enrolled in a trial that compared conservative oxygen therapy with usual oxygen therapy in 1000 mechanically ventilated ICU patients. The primary end point for the current analysis was 90-day mortality. Key secondary outcomes were cause-specific mortality, ICU and hospital length of stay, ventilator-free days, vasopressor-free days, and the proportion of patients receiving renal replacement therapy in the ICU., Results: Patients with sepsis allocated to conservative oxygen therapy spent less time in the ICU with an SpO 2  ≥ 97% (23.5 h [interquartile range (IQR) 8-70] vs. 47 h [IQR 11-93], absolute difference, 23 h; 95% CI 8-38), and more time receiving an FiO 2 of 0.21 than patients allocated to usual oxygen therapy (20.5 h [IQR 1-79] vs. 0 h [IQR 0-10], absolute difference, 20 h; 95% CI 14-26). At 90-days, 47 of 130 patients (36.2%) assigned to conservative oxygen and 35 of 120 patients (29.2%) assigned to usual oxygen had died (absolute difference, 7 percentage points; 95% CI - 4.6 to 18.6% points; P = 0.24; interaction P = 0.35 for sepsis vs. non-sepsis). There were no statistically significant differences between groups for secondary outcomes but point estimates of treatment effects consistently favored usual oxygen therapy., Conclusions: Point estimates for the treatment effect of conservative oxygen therapy on 90-day mortality raise the possibility of clinically important harm with this intervention in patients with sepsis; however, our post hoc analysis was not powered to detect the effects suggested and our data do not exclude clinically important benefit or harm from conservative oxygen therapy in this patient group., Clinical Trials Registry: ICU-ROX Australian and New Zealand Clinical Trials Registry number ACTRN12615000957594.

Renal tissue hypoxia has been implicated as a critical mediatory factor in multiple forms of acute kidney injury (AKI), including in sepsis. In sepsis, whole-kidney measures of macrocirculatory flow and oxygen delivery appear to be poor predictors of microcirculatory abnormalities. Studies in experimental hyperdynamic septic AKI have shown that the renal medulla is particularly susceptible to hypoxia early in sepsis, even in the presence of increased global renal blood flow and oxygen delivery. It has been proposed that an early onset of progressive renal medullary hypoxia, leading to oxidative stress and inflammation, can initiate a downward spiral of cellular injury culminating in AKI. Recent experimental studies have shown that clinical therapies for septic AKI, including, fluids, vasopressors, and diuretics, have distinct effects on renal macrocirculation and microcirculation. Herein, we review the clinical and experimental evidence of alterations in global and regional kidney perfusion and oxygenation during septic AKI and associated therapies. We justify the need for investigation of the effects of therapies on renal microcirculatory perfusion and oxygenation. We propose that interventions that do not worsen the underlying renal pathophysiologic and reparative processes in sepsis will reduce the development and/or progression of AKI more effectively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Mortality in intensive care unit (ICU) patients with acute kidney injury (AKI) remains high. Previous studies have explored the role of HMG-CoA reductase inhibitors (statins) with variable findings., Methods: The Randomized Evaluation of Normal versus Augmented Level Replacement Therapy (RENAL) Study recruited 1508 participants requiring dialysis in ICU between 2006 and 2009. Statin use was recorded at study baseline. Multivariate Cox modelling was used to assess associations of such statin use and all-cause mortality. Propensity score analysis was performed for sensitivity analysis. The primary outcome was all-cause mortality at 90 days., Results: Of the 1462 participants with the available data on statin usage, 187 (12.8%) received statin therapy at baseline. Participants who receiving statins were older (P < 0.001), less likely to have sepsis or require mechanical ventilation (P < 0.001). Multivariable analysis showed statin use did not have significant associations with mortality at both day 28 (hazard ratio (HR) = 1.053, 95% confidence interval (CI) = 0.784-1.415, P = 0.730) and day 90 (HR = 1.091, 95% CI = 0.836-1.424, P = 0.520). Propensity score analysis confirmed the lack of association between statin use and mortality at day 90 (HR = 1.042, 95% CI = 0.734-1.479, P = 0.819). However, in septic patients, multivariable analysis suggested statin therapy was associated with a trend to higher mortality at day 90 (HR = 1.688, 95% CI = 1.132-2.519, P = 0.010) and continuation of statins was associated with higher mortality (HR = 2.160, 95% CI = 1.296-3.599, P = 0.003), compared with statin withdrawal., Conclusion: In the RENAL study cohort, baseline statin use was not associated with mortality. Our findings do not support a protective role of statins in ICU patients with severe AKI. Clinical Trials registration number for the RENAL study: NCT00221013, the date of registration: September 14, 2005., (© 2019 Asian Pacific Society of Nephrology.)

Objective: To describe the prevalence of low-normal body temperatures in emergency department (ED) patients presenting with severe infection, and to determine whether active warming is used in this setting., Design, Setting and Participants: We performed a singlecentre retrospective cohort study in ED patients with community-acquired infection who required admission to the intensive care unit (ICU). Temperatures recorded from presentation up until 24 hours in the ICU were extracted from the patients' clinical records. Body temperatures were then classified as low (≤ 36.4°C), normothermic (36.5-37.9°C) or fever ≥ 38°C., Results: Over the study period, 574 patients were admitted to the ICU with infection. Of them, 151 fulfilled the inclusion criteria, and the in-hospital mortality rate for these patients was 8.6%. On presentation, 22.5% (34 patients) had a low body temperature (35-35.9°C for six patients, and < 35.0°C for three patients). In contrast, 26.5% (40 patients) had a temperature ≥ 38.0°C. Among those who presented with low temperature, the median time to reach normothermia was 7.9 hours (range, 3.3-14.0 hours). Active warming was only applied to one patient, (whose body temperature was < 35°C)., Conclusion: Among patients with community-acquired infection requiring ICU admission, about a quarter have a low temperature and active warming was essentially not applied. These findings suggest that active warming of such patients would likely achieve separation from usual care.

Objective: To assess the effects of sepsis and exogenous insulin on C-peptide levels and C-peptide to insulin ratios in intensive care unit (ICU) patients with type 2 diabetes mellitus (T2DM)., Design, Setting and Participants: In this prospective, observational, single-centre study, we enrolled 31 ICU-admitted adults with T2DM. We measured serum C-peptide and insulin levels during the first 3 days of ICU stay and recorded characteristics of exogenous insulin therapy. Patients were compared on the basis of the presence of sepsis, and their exposure to exogenous insulin therapy. C-peptide levels were also measured in eight healthy subjects., Main Outcome Measures: Serum insulin and C-peptide levels during the first 3 days in ICU., Results: Median C-peptide levels were higher in the ICU population compared with healthy subjects (10.9 [IQR, 8.2 -14.1] v 4.8 [IQR, 4.6-5.1] nmol/L, P < 0.01). Sepsis was present in 25 ICU patients (81%). Among ICU patients unexposed to exogenous insulin, the 11 patients with sepsis had higher median C-peptide levels compared with the six non-septic patients (2.5 [IQR, 1.8-3.7] v 1.7 [IQR, 0.8-2.2] nmol/L, P = 0.04), and a threefold higher C-peptide to insulin ratio (45 [IQR, 37-62] v 13 [IQR, 11-17], P = 0.03). However, septic patients exposed to exogenous insulin had lower median C-peptide levels (1.2 [IQR, 0.7-2.3] nmol/L, P = 0.01) and C-peptide to insulin ratios (5 [IQR, 2-10], P < 0.01) compared with insulin-free septic patients. The C-peptide to insulin ratio was significantly associated with white cell count and severity of illness in insulin-free septic patients., Conclusion: C-peptide levels were elevated in critically ill patients with T2DM. In this population, sepsis increased C-peptide levels and uncoupled serum C-peptide and insulin levels. Exogenous insulin decreased both C-peptide levels and C-peptide to insulin ratios.

Objectives: Persistent critical illness (PerCI) is associated with high mortality and discharge to institutional care. Little is known about factors involved in its progression, complications and cause of death. We aimed to identify such factors and the time when the original illness was no longer the reason for intensive care unit (ICU) stay., Design: Retrospective matched case-control study using an accepted PerCI definition (> 10 days in ICU)., Setting: Single-centre tertiary metropolitan ICU., Participants: All adult patients admitted during a 2-year period were eligible, matched on diagnostic code, gender, age and risk of death., Main Results: Seventy-two patients staying > 10 days (PerCI cases) were matched to 72 control patients. The original illness was no longer a cause for continued ICU stay after a median of 10 days (interquartile range [IQR], 7-16) versus 2 days (IQR, 0-3); P < 0.001. Patients with PerCI were more likely to develop new sepsis (52.8% v 23.6%; P < 0.001), delirium (37.5% v 9.7%; P < 0.001), ICU-acquired weakness (15.3% v 0%, P = 0.001), and to be discharged to chronic care or rehabilitation (37.5% v 16.7%; P < 0.005). Death resulting from sepsis with multi-organ failure occurred in 16.7% v 8.3% of control patients ( P = 0.13), and one-third of patients with PerCI were not mechanically ventilated on Day 10., Conclusion: PerCI likely results from complications acquired after ICU admission and mostly unrelated to the original illness; by Day 10, the original illness does not appear to be its cause, and new sepsis appears an important association.

Objective: There is uncertainty about the optimal i.v. fluid volume and timing of vasopressor commencement in the resuscitation of patients with sepsis and hypotension. We aim to study current resuscitation practices in EDs in Australia and New Zealand (the Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In Emergency Department Sepsis [ARISE FLUIDS] observational study)., Methods: ARISE FLUIDS is a prospective, multicentre observational study in 71 hospitals in Australia and New Zealand. It will include adult patients presenting to the ED during a 30 day period with suspected sepsis and hypotension (systolic blood pressure <100 mmHg) despite at least 1000 mL fluid resuscitation. We will obtain data on baseline demographics, clinical and laboratory variables, all i.v. fluid given in the first 24 h, vasopressor use, time to antimicrobial administration, admission to intensive care, organ failure and in-hospital mortality. We will specifically describe (i) the volume of fluid administered at the following time points: when meeting eligibility criteria, in the first 6 h, at 24 h and prior to vasopressor commencement and (ii) the frequency and timing of vasopressor use in the first 6 h and at 24 h. Screening logs will provide reliable estimates of the proportion of ED patients meeting eligibility criteria for a subsequent randomised controlled trial., Discussion: This multicentre, observational study will provide insight into current haemodynamic resuscitation practices in patients with sepsis and hypotension as well as estimates of practice variation and patient outcomes. The results will inform the design and feasibility of a multicentre phase III trial of early haemodynamic resuscitation in patients presenting to ED with sepsis and hypotension., (© 2019 Australasian College for Emergency Medicine.)

AKI is a common complication of sepsis and is significantly associated with mortality. Sepsis accounts for more than 50% of the cases of AKI, with a mortality rate of up to 40%. The pathogenesis of septic AKI is complex, but there is emerging evidence that, at least in the first 48 hours, the defects may be functional rather than structural in nature. For example, septic AKI is associated with an absence of histopathological changes, but with microvascular abnormalities and tubular stress. In this context, renal medullary hypoxia due to redistribution of intra-renal perfusion is emerging as a critical mediator of septic AKI. Clinically, vasopressor drugs remain the cornerstone of therapy for maintenance of blood pressure and organ perfusion. However, in septic AKI, there is insensitivity to vasopressors such as norepinephrine, leading to persistent hypotension and organ failure. Vasopressin, angiotensin II, and, paradoxically, α 2 -adrenergic receptor agonists (clonidine and dexmedetomidine) may be feasible adjunct therapies for catecholamine-resistant vasodilatory shock. In this review, we outline the recent progress made in understanding how these drugs may influence the renal microcirculation, which represents a crucial step toward developing better approaches for the circulatory management of patients with septic AKI., (© 2018 John Wiley & Sons Ltd.)

Objectives: To examine the effects of fluid bolus therapy on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, PO2, renal function, and fluid balance in experimental early septic acute kidney injury., Design: Interventional study., Setting: Research institute., Subjects: Adult Merino ewes., Interventions: Implantation of flow probes on the pulmonary and renal arteries and laser Doppler oxygen-sensing probes in the renal cortex, medulla, and within a bladder catheter in sheep. Infusion of Escherichia coli to induce septic acute kidney injury (n = 8). After 24, 25, and 26 hours of sepsis, fluid bolus therapy (500 mL of Hartmann's solution over 15 min) was administered., Measurements and Main Results: In conscious sheep, infusion of Escherichia coli decreased creatinine clearance and increased plasma creatinine, renal blood flow (+46% ± 6%) and cortical perfusion (+25% ± 4%), but medullary perfusion (-48% ± 5%), medullary PO2 (-56% ± 4%), and urinary PO2 (-54% ± 3%) decreased (p < 0.01). The first fluid bolus therapy increased blood pressure (+6% ± 1%), central venous pressure (+245% ± 65%), cardiac output (+11% ± 2%), medullary PO2 (+280% ± 90%), urinary PO2 (+164% ± 80%), and creatinine clearance (+120% ± 65%) at 30 minutes. The following two boluses had no beneficial effects on creatinine clearance. The improvement in medullary oxygenation dissipated following the third fluid bolus therapy. Study animals retained 69% of the total volume and 80% of sodium infused. Throughout the study, urinary PO2 correlated significantly with medullary PO2., Conclusions: In early experimental septic acute kidney injury, fluid bolus therapy transiently improved renal function and medullary PO2, as also reflected by increased urinary PO2. These initial effects of fluid bolus therapy dissipated within 4 hours, despite two additional fluid boluses, and resulted in significant volume retention.